Gene-environment interactions between workers'genotypes and hazardous exposures in the workplace are hypothesized to be important for identifying those workers at the highest risk for developing occupational diseases and for targeting potential interventions to reduce that risk and prevent disease. A possible model system for studying this paradigm in occupational carcinogenesis is provided by workers exposed to the carcinogen vinyl chloride (VC) and at risk for the development of angiosarcomas of the liver (ASLs). VC is metabolized (by CYP2E1) to reactive intermediates that generate pro-mutagenic etheno-DNA adducts that can be removed by base excision repair (via XRCC1) or nucleotide excision repair (via XPD), or, if not repaired, result in specific mutations in cancer-related genes (the ras oncogene and the TP53 tumor suppressor gene) that are detectable as circulating mutant protein biomarkers in exposed workers (mutant ras-p21 protein and mutant p53 protein or autoantibodies to mutant p53 protein, respectively). Our epidemiologic studies to date of VC workers demonstrate a statistically significant association between inherited polymorphisms in several genes (CYP2E1, XRCC1 and XPD) and the occurrence of these biomarkers of acquired genetic damage independent of cumulative VC exposure. Experimental studies to date have provided the biological plausibility for this effect of polymorphisms in CYP2E1 and XRCC1, but the largest genetic attributable risk appears to be due to XPD polymorphisms. Thus, the aim of this revised competing continuation proposal is to demonstrate similar biological plausibility for polymorphisms in XPD on susceptibility to VC-induced genetic damage using an array of experimental in silico, in vitro and in vivo approaches. Once workers are identified as high-risk due to their inherited or acquired genetic defects, interventions targeted at these specific defects can be developed to treat or prevent the resultant cancers in future studies. Since VC is one of the highest production volume chemicals in the world with large numbers of workers exposed, study of the health effects of workers in this major manufacturing sector of the economy are an important target for study under the NIOSH National Occupational Research Agenda. Furthermore, since these same pathways are involved in the genetic damage due to many other workplace chemicals, this study could have wider significance for gene-environment interactions/interventions in the workplace generally. PUBLIC HEALTH RELEVANCE: This proposal has significant Public Health Relevance because tens of thousands of workers in the U.S. and millions of workers worldwide are potentially exposed to the carcinogen vinyl chloride. The goal of this revised competing continuation proposal is to document genetic factors in DNA nucleotide excision repair pathways that are critical for mediating the interaction between the workers and this carcinogenic exposure that increase their risk of cancer. This has relevance not only for improving the health of workers exposed to vinyl chloride but also for workers in a range of industries because similar interactions occur with exposures to a host of other workplace toxins.